WO2022087030A1 - Méthodes de traitement de trouble du spectre autistique - Google Patents
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Definitions
- the present disclosure is related to metabolites, e.g., metabolites from bacterial species, and using metabolites for treating autism spectrum disorder in a subject.
- Autism spectrum disorder is a neurodevelopmental condition characterized by social and behavioral impairments.
- ASD Autism spectrum disorder
- ASD subjects frequently suffer from gastrointestinal abnormalities implying a possible link between the gut microbiome and ASD gastrointestinal pathophysiology.
- animal models and human fecal microbiota transplant trials suggesting causal relationships, the impact of intestinal microbial metabolism on the gut-brain axis is gaining increased attention for drug discovery purposes.
- Small molecules produced or converted by the intestinal microbes are of particular interest as they could not only act locally in the intestine but also have the potential to pass the gut barrier and further the blood-brain barrier to directly modulate brain activity related to the disease phenotype.
- SUMMARY [0005] Provided herein are methods for treating autism spectrum disorder in a subject including administering to the subject a composition including a therapeutically effective amount of two or more metabolites selected from the group consisting of: glutamate, malate, ursodeoxycholate, 5-dodecenoate, N-acetyl-L-glutamate, citrate, glycodeoxycholate, and carboxyethyl aminobutyric acid (CEGABA).
- a composition including a therapeutically effective amount of two or more metabolites selected from the group consisting of: glutamate, malate, ursodeoxycholate, 5-dodecenoate, N-acetyl-L-glutamate, citrate, glycodeoxycholate, and carboxyethyl aminobutyric acid (CEGABA).
- Also provided herein are methods treating autism spectrum disorder in a subject including (a) detecting a dysbiosis associated with autism spectrum disorder in a sample from the subject; and (b) administering to the subject a composition including one or more metabolites selected from the group consisting of: glutamate, malate, ursodeoxycholate, 5-dodecenoate, N-acetyl-L-glutamate, citrate, glycodeoxycholate, and carboxyethyl aminobutyric acid (CEGABA).
- the composition comprises two, three, four, or more metabolites.
- the composition comprises a therapeutically effective amount of glutamate, malate, ursodeoxycholate, 5-dodecenoate, N-acetyl-L-glutamate, citrate, glycodeoxycholate, or carboxyethyl aminobutyric acid (CEGABA).
- glutamate malate, ursodeoxycholate, 5-dodecenoate, N-acetyl-L-glutamate, citrate, glycodeoxycholate, or carboxyethyl aminobutyric acid (CEGABA).
- Also provided herein are methods for treating autism spectrum disorder in a subject including administering to the subject a composition comprising two or more bacterial species selected from the group consisting of: Bifidobacterium bifidum, Eggerthella lenta, Eisenbergiella massilien, Prevotella copri, Romboutsia timonensis, Blautia wexlerae, Ruminiclostridium siraeum, Bacteroides intestinalis, Faecalicatena lactari, Dialister invisus, and Ruminococcus callidus.
- Also provided herein are methods treating autism spectrum disorder in a subject including (a) detecting a dysbiosis associated with autism spectrum disorder in a sample from the subject; and (b) administering to the subject a composition comprising two or more bacterial species selected from the group consisting of: Bifidobacterium bifidum, Eggerthella lenta, Eisenbergiella massilien, Prevotella copri, Romboutsia timonensis, Blautia wexlerae, Ruminiclostridium siraeum, Bacteroides intestinalis, Faecalicatena lactari, Dialister invisus, and Ruminococcus callidus.
- a composition comprising two or more bacterial species selected from the group consisting of: Bifidobacterium bifidum, Eggerthella lenta, Eisenbergiella massilien, Prevotella copri, Romboutsia timonensis, Blautia wexlerae, Ru
- Also provided herein are methods of treating autism spectrum disorder or modulating anxiety in a subject including administering to the subject a composition comprising two or more bacterial species of a bacterial family selected from the group consisting of: Streptococcaceae, Lachnospiraceae, Ruminococcaceae, Bacteroidaceae, Butyricicoccaceae, and Pasteurellaceae.
- Also provided herein are of treating autism spectrum disorder or modulating anxiety in a subject including (a) detecting a dysbiosis associated with autism spectrum disorder in a sample from the subject; and (b) administering to the subject a composition comprising two or more bacterial species of a bacterial family selected from the group consisting of: Streptococcaceae, Lachnospiraceae, Ruminococcaceae, Bacteroidaceae, Butyricicoccaceae, and Pasteurellaceae.
- the two or more bacterial species are of a bacterial genera selected from the group consisting of: Streptococcus, Blautia, Haemophilus, Faecalibacterium, Bacteroides, Roseburia, Fusicatenibacter, Lachnospira, and Agathobaculum.
- the two or more bacterial species are of a bacterial species selected from the group consisting of: Blautia wexlerae, Bacteroides valgatus, Bacteroides ovatus, Roseburia inulinivorans, Roseburia intestinalis, Fusicatenibacter saccharivorans, and Agathobaculum butyriciproducens.
- the two or more bacterial species has a 16S rRNA selected from the group consisting of: SEQ ID NO 1-13.
- Any of methods provided herein can also include detecting a dysbiosis associated with autism spectrum disorder in a sample from the subject.
- the sample is a fecal sample.
- detecting the dysbiosis associated with autism spectrum disorder includes determining bacterial gene expression in the sample from the subject.
- detecting the dysbiosis associated with autism spectrum disorder includes determining bacterial composition in the sample from the subject.
- detecting the dysbiosis associated with autism spectrum disorder comprises determining that a bacterial species from the Akkermansiaceae family, Lachnospiraceae family, Streptococcaceae family, Pasteurellaceae family, Ruminococcaceae family, Bacteroidaceae family, Butyricicoccaceae family, Streptococcus genus, Blautia genus, Haemophilus genus, Faecalibacterium genus, Bacteroides genus, Roseburia genus, Fusicatenibacter genus, Lachnospira genus, Agathobaculum genus or a combination thereof that is depleted in the sample from the subject.
- the bacterial species that is depleted in the sample from the subject is selected from the group consisting of: Blautia wexlerae, Bacteroides valgatus, Bacteroides ovatus, Roseburia inulinivorans, Roseburia intestinalis, Fusicatenibacter saccharivorans, and Agathobaculum butyriciproducens.
- detecting the dysbiosis associated with autism spectrum disorder comprises determining that a bacterial species from the Bacteroidaceae family, Lachnospiraceae family, Oscillospiraceae family, Anaerovoraceae family, Eryysipelotrichaceae family, Christensenellaceae family, Bacteriodes genus, Blautia genus, Holdemania genus, Borkfalki genus, Anaerotignum genus, Faecalicatena genus, or a combination thereof is enriched in the sample from subject.
- the bacterial species that is enriched in the sample from the subject is selected from the group consisting of: Bacteroides thetaiotaomicron, Borfalki ceftriaxensis, and Faecalicatena torques.
- the subject has severe autism.
- severe autism is identified using the Mobile Autism Risk Assessment (MARA).
- MARA Mobile Autism Risk Assessment
- the method comprises administering the composition to the subject once, twice, or three times per day.
- the composition is formulated for oral administration, optionally as a tablet, a capsule, a powder, or a liquid.
- Any of the methods provided herein can also include administering another treatment for autism spectrum disorder to the subject.
- the subject was previously identified as having autism spectrum disorder.
- the subject is a human.
- compositions including two or more metabolites selected from the group consisting of: glutamate, malate, ursodeoxycholate, 5- dodecenoate, N-acetyl-L-glutamate, citrate, glycodeoxycholate, and carboxyethyl aminobutyric acid (CEGABA).
- the composition comprises three, four, or more metabolites.
- the composition comprises a therapeutically effective amount of glutamate, malate, ursodeoxycholate, 5-dodecenoate, N-acetyl-L-glutamate, citrate, glycodeoxycholate, carboxyethyl aminobutyric acid (CEGABA).
- glutamate malate
- ursodeoxycholate 5-dodecenoate
- N-acetyl-L-glutamate citrate
- glycodeoxycholate carboxyethyl aminobutyric acid (CEGABA).
- compositions including two or more bacterial species selected from the group consisting of: Bifidobacterium bifidum, Eggerthella lenta, Eisenbergiella massilien, Prevotella copri, Romboutsia timonensis, Blautia wexlerae, Ruminiclostridium siraeum, Bacteroides intestinalis, Faecalicatena lactari, Dialister invisus, and Ruminococcus callidus.
- compositions including two or more bacterial species of a bacterial family selected from the group consisting of: Streptococcaceae, Lachnospiraceae, Ruminococcaceae, Bacteroidaceae, Butyricicoccaceae, and Pasteurellaceae.
- the two or more bacterial species are of a bacterial genera selected from the group consisting of: Streptococcus, Blautia, Haemophilus, Faecalibacterium, Bacteroides, Roseburia, Fusicatenibacter, Lachnospira, and Agathobaculum.
- the two or more bacterial species are of a bacterial species selected from the group consisting of: Blautia wexlerae, Bacteroides valgatus, Bacteroides ovatus, Roseburia inulinivorans, Roseburia intestinalis, Fusicatenibacter saccharivorans, and Agathobaculum butyriciproducens.
- the composition is formulated for oral administration, optionally as a tablet, a capsule, a powder, or a liquid. In some embodiments, the composition is administered to a subject once, twice, or three times per day.
- an "effective amount” or a “therapeutically effective amount” of an active agent or ingredient, or pharmaceutically active agent or ingredient refer to an amount of the pharmaceutically active agent sufficient enough to reduce or eliminate one or more symptoms of the disorder or to effect a cure upon administration. Effective amounts of the pharmaceutically active agent will vary with the kind of pharmaceutically active agent chosen, the particular condition or conditions being treated, the severity of the condition, the duration of the treatment, the specific components of the composition being used, and like factors.
- an "effective amount” or a “therapeutically effective amount” of an active agent or ingredient, or pharmaceutically active agent or ingredient can also refer to an amount of a combination of two or more active agents or a combination of an active agent and another treatment (e.g., behavioral therapy, psychological therapy, and educational therapy) sufficient to reduce or eliminate one or more symptoms of the disorder or in some cases, to effect a cure upon administration.
- another treatment e.g., behavioral therapy, psychological therapy, and educational therapy
- a "therapeutically effective amount" of an active agent can refer to an amount of a combination of active agents or a combination of an active agent and another treatment (e.g., behavioral therapy, psychological therapy, and educational therapy) when an additive or synergistic effect is observed with the combination compared to administration of the active agent(s) and/or treatment(s) of autism spectrum disorder alone.
- another treatment e.g., behavioral therapy, psychological therapy, and educational therapy
- an effective amount of a bacterial species can refer to an amount of the bacterial species sufficient to reduce or eliminate one or more symptoms of the disorder or in some cases, to effect a cure upon administration.
- Effective amounts of a bacterial species will vary with the bacterial species chosen, the particular condition or conditions being treated, the severity of the condition, the duration of the treatment, the specific components of the composition being used, and like factors.
- An "effective amount” can also refer to an amount of a combination of two or more bacterial species or a combination of a bacterial species and another treatment and/or other adjunct therapy sufficient to reduce or eliminate one or more symptoms of the disorder or in some cases, to effect a cure upon administration.
- an "effective amount” can refer to an amount of a combination of bacterial species or a combination of a bacterial species and another treatment (e.g., a therapeutic agent) when an additive or synergistic effect is observed with the combination compared to administration of the bacterial species and/or treatment(s) of autism spectrum disorder alone.
- subject or “patient” refers to any subject, particularly a mammalian subject such as a human, for whom diagnosis, prognosis, or therapy is desired.
- “treatment” or “treating" of a disease, disorder, or condition encompasses alleviation of at least one symptom thereof, a reduction in the severity thereof, or the delay or inhibition of the progression thereof.
- Treatment need not mean that the disease, disorder, or condition is totally cured.
- a useful composition herein needs only to reduce the severity of a disease, disorder, or condition, reduce the severity of one or more symptoms associated therewith, or improve a patient or subject's quality of life.
- the term "preventing” as used herein means the prevention of the onset, recurrence, or spread, in whole or in part, of the disease or condition as described herein, or a symptom thereof.
- administration or “administering” refers to a method of giving an amount of an active agent, or a composition thereof, a bacterial species, or a composition thereof, or a treatment of autism spectrum disorder and/or other adjunct therapy to a subject.
- the method of administration can vary depending on various factors, e.g., the components of the composition, the site of the disease, and the severity of the disease.
- "Microbiome” refers to the collection of microorganisms and viruses and/or their genes from a given environment.
- microbiome can refer to the collection of the microorganisms and viruses and/or their genes from the gastrointestinal tract of humans.
- “Microbiota” refers to the microorganisms in a specific environment.
- Dysbiosis refers to a state of the microbiota or microbiome of the gut or other body area (e.g., mucosal or skin surfaces or any other microbiota niche) of a subject (i.e., the host) in which the diversity and/or function of the ecological network is disrupted, e.g., as compared to the state of the microbiota or microbiome of the gut or other body area in a control population.
- a control population can include individuals that meet one or more qualifications such as individuals that have not been diagnosed with a disease or disorder (e.g., the same disease or disorder as the subject); individuals that do not have a known genetic predisposition to a disease or disorder (e.g., the same disease or disorder as the subject); or individuals that do not have a known environmental predisposition to a disease or disorder (e.g., the same disease or disorder as the subject); or individuals that do not have a known predisposition that would prevent treatment of and/or recovery from a disease or disorder (e.g., the same disease or disorder as the subject).
- the individuals in the control population meet one of the above control population qualifications.
- the individuals in the control population meet two of the above control population qualifications. In some embodiments, the individuals in the control population meet three of the above control population qualifications. In some embodiments, the individuals in the control population meet four of the above control population qualifications. In some embodiments, the control population is homogenous with respect to at least one of the qualifications. Any disruption in the microbiota or microbiome of a subject (i.e., host) compared to the microbiota or microbiome of a control population can be considered a dysbiosis, even if such dysbiosis does not result in a detectable decrease in health of the subject.
- Dysbiosis in a subject may be unhealthy for the subject (e.g., result in a diseased state in the subject), it may be unhealthy for the subject under only certain conditions (e.g., result in diseased state under only certain conditions), or it may prevent the subject from becoming healthier (e.g., may prevent a subject from responding to treatment or recovering from a disease or disorder).
- Dysbiosis may be due to a decrease in diversity of the microbiota population composition (e.g., a depletion of one or more bacterial species, an overgrowth of one or more bacterial species, or a combination thereof), the overgrowth of one or more population of pathogens (e.g., a population of pathogenic bacteria) or pathobionts, the presence of and/or overgrowth of a symbiotic organism able to cause disease only when certain genetic and/or environmental conditions are present in a subject, or a shift to an ecological network that no longer provides a beneficial function to the host and therefore no longer promotes health.
- the terms "microorganism” or "microbe” should be taken broadly.
- the disclosure refers to a "bacterium” or a "microbe.” This characterization can refer to not only the identified taxonomic bacterial genera of the microbe, but also the identified taxonomic species, as well as the bacterial species.
- a "strain" can include descendants of a single isolation in pure culture that is usually made up of a succession of cultures ultimately derived from an initial single colony.
- a strain includes an isolate or a group of isolates that can be distinguished from other isolates of the same genus and species by phenotypic characteristics, genotypic characteristics, or both.
- relative abundance is the number or percentage of a microbe present in the gastrointestinal tract or any other microbiota niche of a subject, such as the ocular, placental, lung, cutaneous, urogenital, or oral microbiota niches, relative to the number or percentage of total microbes present in the gastrointestinal tract or the other microbiota niche of the subject.
- the relative abundance may also be determined for particular types of microbes such as bacteria, fungi, viruses, and/or protozoa, relative to the total number or percentage of bacteria, fungi, viruses, and/or protozoa present.
- Relative abundance can be determined by a number of methods readily known to the ordinarily skilled artisan, including, but not limited to, array or microarray hybridization, sequencing, quantitative PCR, and culturing and performance of colony forming unit (cfu, CFU) assays or plaque forming unit (pfu, PFU) assays performed on a sample from the gastrointestinal tract or other microbiota niche.
- an isolated microbe e.g., a bacterial species
- an isolated microbe may exist as, for example, a biologically pure culture, or as spores (or other forms of the bacterial species) in association with a pharmaceutically acceptable excipient suitable for human administration.
- more than one microbe can be isolated.
- isolated microbes can refer to a mixture of two or more microbes that have been separated from at least one of the materials with which they are associated in a particular environment.
- the isolated microbes exist as isolated and biologically pure cultures.
- biologically pure refers to a composition comprising a species or strains of a microbe, wherein the composition is substantially free from the material from which the microbe was isolated or produced and from other microbes (e.g., other species or strains and other microbes of a different taxonomic classification).
- biologically pure can refer to a composition that comprises a strain of a bacterial species that is substantially free from the material from which the bacterial species was isolated or produced and from other microbes, e.g., other strains of the same bacterial species, other species of the same bacteria, and other bacteria and/or microbes of a different taxonomic classification). It will be appreciated by one of skill in the art, that an isolated and biologically pure culture of a particular microbe, denotes that said culture is substantially free (within scientific reason) of other living organisms and contains only the individual microbe in question.
- substantially free means that a composition comprising a species or strain of a microbe is at least about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or more than about 99% free of the material from which the microbe was isolated or produced and from other microbes.
- a biologically pure composition contains no other bacterial species in quantities that can be detected by typical bacteriological techniques.
- probiotic refers to a substantially pure microbe (i.e., a single isolate) or a mixture of microbes, and may also include any additional components that can be administered to a subject (e.g., a human), for restoring or altering the microbiota or microbiome in the subject.
- a probiotic or microbial inoculant composition can be administered with an agent to allow the microbe(s) to survive the environment of the gastrointestinal tract, i.e., to resist low pH and/or to grow in the gastrointestinal environment.
- a composition as described herein includes a probiotic.
- prebiotic refers to an agent that increases the number and/or activity of one or more microbes.
- microbes can include microbes for restoring or altering the microbiota or microbiome of a subject.
- a prebiotic include a fructooligosaccharide (e.g., oligofructose, inulin, or an inulin-type fructan), a galactooligosaccharide, an amino acid, an alcohol. See, for example, Ramirez-Farias et al. (2008. Br. J Nutr.4:1-10 and Pool-Zobel and Sauer (2007. J Nutr.137:2580-2584).
- a “live biotherapeutic product” or “LBP” refers to a biological product that: 1) contains live organisms, such as bacteria, and 2) is applicable to the prevention, treatment, and/or cure of a disease or condition of a subject.
- a "combination" of two or more bacteria, e.g., bacterial species, can refer to the physical co-existence of the bacteria, either in the same material or product.
- a combination of two or more bacteria can include the temporal co- administration or co-localization of the two or more bacteria.
- a bacterial species genomic sequence will contain multiple copies of 16S rRNA sequences.
- the 16S rRNA sequences can be used for making distinctions between genera, species and strains. For example, if one or more of the 16S rRNA sequences shares less than 97% sequence identity from a reference sequence, then the two organisms from which the sequences were obtained can be of different species or strains. [0043] "Percentage of sequence identity" is determined by comparing two optimally aligned sequences over a comparison window, wherein the portion of the polynucleotide or polypeptide sequence in the comparison window may comprise additions or deletions (i.e., gaps) as compared to the reference sequence (which does not comprise additions or deletions) for optimal alignment of the two sequences.
- the percentage is calculated by determining the number of positions at which the identical nucleic acid base or amino acid residue occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the window of comparison and multiplying the result by 100 to yield the percentage of sequence identity.
- nucleic acids or polypeptide sequences refer to two or more sequences or subsequences that are the same or have a specified percentage of amino acid residues or nucleotides that are the same (i.e., about 60% identity, preferably 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or higher identity over a specified region, when compared and aligned for maximum correspondence over a comparison window or designated region) as measured using a BLAST or BLAST 2.0 sequence comparison algorithms with default parameters described below, or by manual alignment and visual inspection (see, e.g., NCBI web site ncbi.nlm.nih.gov/BLAST/ on the world wide web or the like).
- sequences are then said to be “substantially identical.”
- This definition also refers to, or may be applied to, the compliment of a test sequence.
- the definition also includes sequences that have deletions and/or additions, as well as those that have substitutions.
- the preferred algorithms can account for gaps and the like.
- identity exists over a region that is at least about 25 amino acids or nucleotides in length, or more preferably over a region that is 50-100 amino acids or nucleotides in length.
- combination therapy refers to a dosing regimen of one or more active agents (e.g., a metabolite) and one or more other treatments of autism spectrum disorder during a period of time, wherein the active agent(s) and other treatment (e.g., behavioral therapy, psychological therapy, educational therapy, a prebiotic, a probiotic, or a combination thereof) are administered together or separately in a manner prescribed by a medical care taker or according to a regulatory agency.
- active agents e.g., a metabolite
- other treatment e.g., behavioral therapy, psychological therapy, educational therapy, a prebiotic, a probiotic, or a combination thereof
- a combination therapy can be administered to a patient for a period of time.
- the period of time occurs following the administration of one or more of: a different bacterial species, a different treatment/ therapeutic agent, and a different combination of treatments/therapeutic agents to the subject. In some embodiments, the period of time occurs before the administration of one or more of: a different active agent, a different treatment, and a different combination of treatments/therapeutic agents to the subject.
- the term "fixed combination" means that one or more active agents as described herein, or a composition thereof, and at least one other treatment (e.g., a prebiotic, a probiotic, or a combination thereof), are both administered to a subject simultaneously in the form of a single composition or dosage.
- non-fixed combination means that one or more active agents as described herein, or a composition thereof, and at least one other treatment (e.g., a prebiotic, a probiotic, or a combination thereof) are formulated as separate compositions or dosages such that they may be administered to a subject simultaneously or sequentially with variable intervening time limits. These also apply to cocktail therapies, e.g., the administration of three or more therapeutic agents.
- cocktail therapies e.g., the administration of three or more therapeutic agents.
- Reference to the term “about” has its usual meaning in the context of compositions to allow for reasonable variations in amounts that can achieve the same effect and also refers herein to a value of plus or minus 10% of the provided value. For example, "about 20" means or includes amounts from 18 to and including 22.
- FIG.1 is an exemplary schematic of the analysis.
- FIG. 2 is table showing cohort information.
- FIG.3 is an exemplary schematic of the analysis.
- FIG.4 is a plot showing alpha diversity measure and ASD severity.
- FIGS.5A and 5B are plots showing relative abundance and ASD severity.
- FIGS. 6A and 6B are plots showing relative abundance of Anaerotignum, Blautia, and Blautia wexlerae at three time points.
- FIGS.7A and 7B are plots showing measured intensity for Metabolites A and B.
- FIGS.8A and 8B are plots showing number of metabolites by class (FIG.8A) and contribution type (FIG.8B).
- FIG.9A is a plot showing pairwise correlation for Metabolite A.
- FIG.9B is a plot showing pairwise correlation for Metabolite B.
- FIG. 10 is a volcano plot comparing the metabolites abundance in the most severe cases of ASD and their neurotypical siblings.
- FIG. 11 is a plot showing mouse weights over time when eating food supplemented with various metabolites.
- FIG.12 is a plot showing the amount of supplemented food mice ate
- FIG.13 is a schematic of an elevated plus maze.
- FIG.14 is a plot of the time (seconds) spent in the closed arms of an elevated plus maze of mice fed food supplemented with various metabolites.
- Control no supplement compound
- 5D supplemented with 5-dodecenoate
- GCD supplemented with glycodeoxycholate
- UDC supplemented with ursodeoxycholate. Significance was determined with a Wilcox test.
- FIG.15 is a plot of the activity time (seconds) in closed arms of an elevated plus maze of mice fed food supplemented with various metabolites.
- FIG.16 is a figure of an exemplary three-chamber sociability test.
- FIG.18 is a plot of the time mice spent in the center of the maze by mice fed food supplemented with various metabolites.
- Control no supplement compound
- 5D supplemented with 5-dodecenoate
- GCD supplemented with glycodeoxycholate
- UDC supplemented with ursodeoxycholate. Significance was determined with a Wilcox test.
- FIG.21 is a schematic of a three-chamber sociability test.
- FIG.22 is a plot of time spent with a novel mouse (‘new’) or a known mouse (‘old’) in a three-chamber sociability test.
- FIG. 24 is a plot of the average distance traveled over time by mice fed food supplemented with various metabolites.
- FIG.25 is a schematic of the study design of Example 4.
- FIG. 26 is a plot showing relative abundance counts of ASVs significantly associated with the ASD cohort in two independent contrast methods.
- FIGs. 27A-27D are plots showing performance and variable importance of binary phenotype classifiers using different subsets of data.
- FIG.27A is a plot showing the performance of predictive models using metadata and ASVs. Grey lines show the relationship between folds in 7 fold cross-validation.
- FIG. 27B is a plot showing the predictive value of individual lifestyle variables. X axis represents change in Gini index upon removal of the variable.
- FIG. 27C is a plot showing performance of predictive models using only ASV inputs.
- the 11 biomarker set (Table 4) classifies with an average ROC AUC of 0.66, and adding additional associated taxa does not significantly increase performance.
- FIG.27D is a plot showing the predictive value of ASVs and their taxonomic annotations.
- FIGs.28A-28C are plots showing correlations between changes in anxiety and log2-fold changes in relative taxa abundance.
- FIG. 28A is a plot showing the change of ASVs abundance correlated with changes in anxiety score across the entire cohort. Positive/negative values on the x axis signify increases/decreases in anxiety respectively between timepoints within an individual.
- FIG.28B is a plot showing ASVs correlated with changes in anxiety scores across both cohorts, and still significant when considering the ASD cohort only.
- FIG.28C is a plot showing ASVs that correlate negatively with anxiety in the ASD cohort also correlate with alpha diversity (Shannon evenness index) of samples.
- ASD autism spectrum disorder
- modulation comorbidities of autism spectrum disorder e.g., anxiety
- ASD is a complex neurodevelopmental brain disorder that can be characterized by behavioral symptoms including impairments in social communication and restricted/repetitive behavior. See, e.g., Eissa et al. Front Neurosci.2018; 12: 304.
- the severity of symptom can vary widely, and they can also be compounded by significant comorbidities including intellectual disability, epilepsy, anxiety, sleep, and gastrointestinal disorders. See Cheroni et al.
- the methods provided herein can include administering to the subject a composition that includes a therapeutically effective amount of a metabolite.
- the composition comprises a therapeutically effective amount of one or more (e.g., two or more, three or more, four or more, five or more, six or more, seven or more) metabolites selected from the group consisting of: glutamate, malate, ursodeoxycholate, 5- dodecenoate, N-acetyl-L-glutamate, citrate, glycodeoxycholate, and carboxyethyl aminobutyric acid (CEGABA).
- one or more e.g., two or more, three or more, four or more, five or more, six or more, seven or more
- CEGABA carboxyethyl aminobutyric acid
- the composition includes a therapeutically effective amount of two or more metabolites selected from the group consisting of: glutamate, malate, ursodeoxycholate, 5-dodecenoate, N-acetyl-L-glutamate, citrate, glycodeoxycholate, and carboxyethyl aminobutyric acid (CEGABA) (e.g., any two, three, four, five, six, seven or all eight of the metabolites described herein).
- CEGABA carboxyethyl aminobutyric acid
- the composition includes a therapeutically effective amount of three or more metabolites selected from the group consisting of: glutamate, malate, ursodeoxycholate, 5- dodecenoate, N-acetyl-L-glutamate, citrate, glycodeoxycholate, and carboxyethyl aminobutyric acid (CEGABA).
- the composition includes a therapeutically effective amount of four or more metabolites selected from the group consisting of: glutamate, malate, ursodeoxycholate, 5-dodecenoate, N-acetyl-L-glutamate, citrate, glycodeoxycholate, and carboxyethyl aminobutyric acid (CEGABA).
- the composition comprises glutamate. In some embodiments, the composition comprises malate. In some embodiments, the composition comprises ursodeoxycholate. In some embodiments, the composition comprises 5- dodecenoate. In some embodiments, the composition comprises N-acetyl-L-glutamate. In some embodiments, the composition comprises citrate. In some embodiments, the composition comprises glycodeoxycholate. In some embodiments, the composition comprises CEGABA. [0085] In some embodiments, the composition comprises a therapeutically effective amount of glutamate. In some embodiments, the composition comprises a therapeutically effective amount of malate. In some embodiments, the composition comprises a therapeutically effective amount of ursodeoxycholate.
- the composition comprises a therapeutically effective amount of 5-dodecenoate. In some embodiments, the composition comprises a therapeutically effective amount of N-acetyl- L-glutamate. In some embodiments, the composition comprises a therapeutically effective amount of citrate. In some embodiments, the composition comprises a therapeutically effective amount of glycodeoxycholate. In some embodiments, the composition comprises a therapeutically effective amount of CEGABA. [0086] In some embodiments, the composition comprises glutamate and one or more of malate, ursodeoxycholate, 5-dodecenoate, N-acetyl-L-glutamate, citrate, glycodeoxycholate, and carboxyethyl aminobutyric acid (CEGABA).
- CEGABA carboxyethyl aminobutyric acid
- the composition comprises malate and one or more of glutamate, ursodeoxycholate, 5-dodecenoate, N-acetyl-L-glutamate, citrate, glycodeoxycholate, and carboxyethyl aminobutyric acid (CEGABA).
- the composition comprises ursodeoxycholate and one or more of glutamate, malate, 5-dodecenoate, N- acetyl-L-glutamate, citrate, glycodeoxycholate, and carboxyethyl aminobutyric acid (CEGABA).
- the composition comprises 5-dodecenoate and one or more of glutamate, malate, ursodeoxycholate, N-acetyl-L-glutamate, citrate, glycodeoxycholate, and carboxyethyl aminobutyric acid (CEGABA).
- the composition comprises N-acetyl-L-glutamate and one or more of glutamate, malate, ursodeoxycholate, 5-dodecenoate, citrate, glycodeoxycholate, and carboxyethyl aminobutyric acid (CEGABA).
- the composition comprises citrate and one or more of glutamate, malate, ursodeoxycholate, 5-dodecenoate, N-acetyl-L-glutamate, glycodeoxycholate, and carboxyethyl aminobutyric acid (CEGABA).
- the composition comprises glycodeoxycholate and one or more of glutamate, malate, ursodeoxycholate, 5-dodecenoate, N-acetyl-L-glutamate, citrate, and carboxyethyl aminobutyric acid (CEGABA).
- the composition comprises CEGABA and one or more of glutamate, malate, ursodeoxycholate, 5-dodecenoate, N-acetyl-L-glutamate, citrate, and glycodeoxycholate.
- the composition comprises a therapeutically effective amount of glutamate and a therapeutically effective amount of one or more of malate, ursodeoxycholate, 5-dodecenoate, N-acetyl-L-glutamate, citrate, glycodeoxycholate, and carboxyethyl aminobutyric acid (CEGABA).
- the composition comprises a therapeutically effective amount of malate and a therapeutically effective amount of one or more of glutamate, ursodeoxycholate, 5-dodecenoate, N-acetyl-L- glutamate, citrate, glycodeoxycholate, and carboxyethyl aminobutyric acid (CEGABA).
- the composition comprises a therapeutically effective amount of ursodeoxycholate and a therapeutically effective amount of one or more of glutamate, malate, 5-dodecenoate, N-acetyl-L-glutamate, citrate, glycodeoxycholate, and carboxyethyl aminobutyric acid (CEGABA).
- the composition comprises a therapeutically effective amount of 5-dodecenoate and a therapeutically effective amount of one or more of glutamate, malate, ursodeoxycholate, N-acetyl-L- glutamate, citrate, glycodeoxycholate, and carboxyethyl aminobutyric acid (CEGABA).
- the composition comprises a therapeutically effective amount of N- acetyl-L-glutamate and a therapeutically effective amount of one or more of glutamate, malate, ursodeoxycholate, 5-dodecenoate, citrate, glycodeoxycholate, and carboxyethyl aminobutyric acid (CEGABA).
- the composition comprises a therapeutically effective amount of citrate and a therapeutically effective amount of one or more of glutamate, malate, ursodeoxycholate, 5-dodecenoate, N-acetyl-L-glutamate, glycodeoxycholate, and carboxyethyl aminobutyric acid (CEGABA).
- the composition comprises a therapeutically effective amount of glycodeoxycholate and a therapeutically effective amount of one or more of glutamate, malate, ursodeoxycholate, 5-dodecenoate, N-acetyl-L-glutamate, citrate, and carboxyethyl aminobutyric acid (CEGABA).
- the composition comprises a therapeutically effective amount of CEGABA and a therapeutically effective amount of one or more of glutamate, malate, ursodeoxycholate, 5-dodecenoate, N-acetyl-L- glutamate, citrate, and glycodeoxycholate.
- the methods provided herein can include administering to the subject a composition that includes a bacterial species.
- the composition comprises one or more bacterial species selected from the group consisting of: Bifidobacterium bifidum, Eggerthella lenta, Eisenbergiella massilien, Prevotella copri, Romboutsia timonensis, Blautia wexlerae, Ruminiclostridium siraeum, Bacteroides intestinalis, Faecalicatena lactaris, Dialister invisus, Ruminococcus callidus, ASV 1597 (Faecalicatena lactaris), and ASV 876 (Dialister invisus . ).
- the bacterial species is depleted in the subject as compared to a control (e.g., identified as a dysbiosis as described herein).
- Faecalicatena lactaris included in a composition provided herein has an amplicon sequencing variant (ASV) sequence from the 16S rRNA gene that is at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%.96%, 97%, 98%, 99%) embodiments, Dialister invisus included in a composition provided herein has an ASV sequence from the 16S rRNA gene that is at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%.
- ASV amplicon sequencing variant
- the composition comprises one or more bacterial species of a bacterial family selected from the group consisting of: Streptococcaceae, Lachnospiraceae, Ruminococcaceae, Bacteroidaceae, Butyricicoccaceae, and Pasteurellaceae.
- the composition one or more bacterial species of a bacterial genera selected from the group consisting of: Streptococcus, Blautia, Haemophilus, Faecalibacterium, Bacteroides, Roseburia, Fusicatenibacter, Lachnospira, and Agathobaculum.
- the composition contains Blautia wexlerae, Bacteroides valgatus, Bacteroides ovatus, Roseburia inulinivorans, Roseburia intestinalis, Fusicatenibacter saccharivorans, and Agathobaculum butyriciproducens.
- the composition comprises Faecalibacterium spp. with a 16S rRNA gene that is at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%.96%, [0092]
- the composition comprises Bacteroides vulgatus with a 16S rRNA gene that is at least 90% (e.g.
- the composition comprises Bacteroides ovatus with a 16S rRNA gene that is at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%.96%, 97%, 98%, 99%) [0093]
- the composition comprises Roseburia inulinivorans with a 16S rRNA gene that is at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%.96%, CC G GGCG GGCGGC C GG CG C G CGC G GGC CG GC GTGGGG).
- the composition comprises Roseburia intestinalis with a 16S rRNA gene that is at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%.96%, 97%, [0094]
- the composition comprises Faecalicatena torques with a 16S rRNA gene that is at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%.96%, 97%, [0095]
- the composition comprises Fusicatenibacter saccharivorans with a 16S rRNA gene that is at least 90% (e.g. at least 91%, 92%, 93%, [0096]
- the composition comprises Lachnospira spp.
- the composition comprises a species of the Lachnospiraceae family with a 16S rRNA gene that is at least 90% (e.g. at least 91%, 92%, [0098]
- the composition comprises Agathobaculum butyriciproducens with a 16S rRNA gene that is at least 90% (e.g.
- the method can include detecting, in a sample from the subject, a dysbiosis associated with autism spectrum disorder, e.g., before administering to the subject a metabolite described herein or a bacterial species described herein.
- the sample is a biological sample.
- the sample is a fecal (stool) sample, a sputum sample, a saliva sample, a mucous sample, a nasal sample, a nasopharyngeal sample, an oral sample, or a respiratory fluid sample.
- the sample is a fecal sample or a stool sample.
- detecting the dysbiosis associated with autism spectrum disorder can include determining a bacterial gene and its expression in the sample from the subject (e.g., fecal sample).
- the bacterial gene and its expression can be determined in the sample from the subject e.g., before administering to the subject a metabolite described herein or a bacterial species described herein and/or after administering to the subject a metabolite described herein or a bacterial species described herein.
- Determining the bacterial gene and its expression can include performing, for example, RNAseq and/or RT-qPCR.
- detecting the dysbiosis associated with autism spectrum disorder comprises determining bacterial composition in the sample from the subject (e.g., fecal sample).
- the bacterial composition can be determined in a sample from the subject, e.g., before administering to the subject a metabolite described herein or a bacterial species described herein and/or after administering to the subject a metabolite described herein or a bacterial species described herein.
- Determining the bacterial composition can include, for example, sequencing one or more nucleic acids from the bacteria or the sample (e.g. fecal or stool sample).
- bacteria can be identified by their 16S rRNA gene sequence.
- detecting the dysbiosis associated with autism spectrum disorder comprises determining that a bacterial species from the Akkermansiaceae family, Lachnospiraceae family, Streptococcaceae family, Pasteurellaceae family, Ruminococcaceae family, Bacteroidaceae family, Butyricicoccaceae family, Streptococcus genus, Blautia genus, Haemophilus genus, Faecalibacterium genus, Bacteroides genus, Roseburia genus, Fusicatenibacter genus, Lachnospira genus, Agathobaculum genus or a combination thereof that is depleted in the sample from the subject (e.g., reduced in the fecal sample or reduced in the gastrointestinal tract of the subject).
- the bacterial species that is depleted in the sample from the subject is selected from the group consisting of: Blautia wexlerae, Bacteroides valgatus, Bacteroides ovatus, Roseburia inulinivorans, Roseburia intestinalis, Fusicatenibacter saccharivorans, and Agathobaculum butyriciproducens.
- the methods can include administering the depleted bacterial species to the subject.
- detecting the dysbiosis associated with autism spectrum disorder comprises determining that a bacterial species from the Bacteroidaceae family, Lachnospiraceae family, Oscillospiraceae family, Anaerovoraceae family, Eryysipelotrichaceae family, Christensenellaceae family, Bacteriodes genus, Blautia genus, Holdemania genus, Borkfalki genus, Anaerotignum genus, Faecalicatena genus, or a combination thereof is enriched in the sample from subject (e.g., increased in the fecal sample or increased in the gastrointestinal tract of the subject).
- the bacterial species that is enriched in the sample from the subject is selected from the group consisting of: Bacteroides thetaiotaomicron, Borfalki ceftriaxensis, and Faecalicatena torques.
- the methods can include administering a treatment to deplete a species that was enriched in the subject, e.g., using antibiotics or phage that are specific to the strain, species, or genera.
- the methods provided herein can include administering a composition described herein (e.g., a composition comprising a metabolite described herein or bacterial species described herein) to the subject at least once per day.
- the composition can be administered two, three, four, or more times per day.
- the method comprises administering a composition described herein (e.g., a composition comprising a metabolite described herein or bacterial species described herein) to the subject daily, every other day, every three days, or once a week.
- a composition described herein e.g., a composition comprising a metabolite described herein or bacterial species described herein
- an effective amount of a metabolite described herein or bacterial species described herein is administered in one dose, e.g., once per day.
- an effective amount of the metabolite described herein or bacterial species described herein is administered in more than one dose, e.g., more than once per day.
- methods provided herein can include administering a composition described herein (e.g., a composition comprising a metabolite described herein or bacterial species described herein) in combination with one or more other treatments of ASD.
- a composition described herein e.g., a composition comprising a metabolite described herein or bacterial species described herein
- other treatments of ASD include: antipsychotic drugs, antidepressants, behavioral therapy, psychological therapy, educational therapy, occupational therapy, and speech therapy.
- Compositions described herein e.g., a composition comprising a metabolite described herein or bacterial species described herein
- any other treatments can be administered together (e.g., in the same formulation), or the composition comprising the bacterial species can be administered concurrently with, prior to, or subsequent to, the one or more other treatments.
- a prebiotic and/or probiotic can be administered in combination with a composition described herein (e.g., a composition comprising a metabolite described herein or bacterial species described herein).
- a probiotic include one of more of Bifidobacteria (e.g., B. animalis, B. breve, B. lactis, B. longum, B. longum, or B. infantis), Lactobacillus (e.g., L. acidophilus, L. reuteri, L. bulgaricus, L. lactis, L. casei, L. rhamnosus, L. plantarum, L. paracasei, or L.
- Bifidobacteria e.g., B. animalis, B. breve, B. lactis, B. longum, B. longum, or B. infantis
- Lactobacillus e.g., L. acidophilus, L. reuteri, L. bulgaricus, L
- Non-limiting examples of a prebiotic include a fructooligosaccharide (e.g., oligofructose, inulin, or an inulin-type fructan), a galactooligosaccharide, an amino acid, or an alcohol. See, for example, Ramirez-Farias et al. (2008. Br. J Nutr.4:1-10) and Pool- Zobel and Sauer (2007. J Nutr.137:2580-2584).
- a fructooligosaccharide e.g., oligofructose, inulin, or an inulin-type fructan
- galactooligosaccharide e.g., an amino acid, or an alcohol. See, for example, Ramirez-Farias et al. (2008. Br. J Nutr.4:1-10) and Pool- Zobel and Sauer (2007. J Nutr.137:2580-2584).
- methods provided herein can include monitoring the subject after treatment with a composition described herein (e.g., a composition comprising a metabolite described herein or bacterial species described herein) to determine if one or more symptoms have been alleviated, if the severity of one or more symptoms has been reduced, or if progression of the disease has been delayed or inhibited in the subject.
- a composition described herein e.g., a composition comprising a metabolite described herein or bacterial species described herein
- Non- limiting examples of autism spectrum disorder symptoms include: making little or inconsistent eye contact; tending not to look at or listen to people; rarely sharing enjoyment of objects or activities by pointing or showing things to others; failing to, or being slow to, respond to someone calling their name or to other verbal attempts to gain attention; having difficulties with the back and forth of conversation; often talking at length about a favorite subject without noticing that others are not interested or without giving others a chance to respond; having facial expressions, movements, and gestures that do not match what is being said; having an unusual tone of voice that may sound sing-song or flat and robot- like; having trouble understanding another person’s point of view or being unable to predict or understand other people’s actions; repeating certain behaviors or having unusual behaviors (e.g., repeating words or phrases (echolalia)); having a lasting intense interest in certain topics, such as numbers, details, or facts; having overly focused interests, such as with moving objects or parts of objects; getting upset by slight changes in a routine; and being more or less sensitive than other people to sensory input, such
- methods provided herein can include monitoring the subject after treatment with a composition described herein (e.g. a composition comprising a metabolite described herein or a bacterial species described herein) to determine if one or more comorbidities have been alleviated or if the severity of one or more comorbidities has been reduced.
- a composition described herein e.g. a composition comprising a metabolite described herein or a bacterial species described herein
- autism spectrum disorder comorbidities include: intellectual disability, epilepsy, anxiety, sleep, and gastrointestinal disorders. See Cheroni et al.
- a composition described herein e.g., a composition comprising a metabolite described herein or bacterial species described herein
- the subject has severe autism.
- the autism severity is measured using the Mobile Autism Risk Assessment (MARA). See, e.g., Duda et al. J Autism Dev Disord.2016; 46: 1953–1961.
- methods provided herein can include administering another treatment for autism spectrum disorder to the subject.
- Non-limiting examples of treatments can include medication, such as antipsychotics (e.g., risperidone or aripipraxole) or stimulants (e.g. methylphenidate, atomoxetine, or clonidine), or therapy, such as behavioral therapy, family counseling, speech and/or language therapy, or educational therapy.
- medication such as antipsychotics (e.g., risperidone or aripipraxole) or stimulants (e.g. methylphenidate, atomoxetine, or clonidine), or therapy, such as behavioral therapy, family counseling, speech and/or language therapy, or educational therapy.
- the compositions described herein e.g., compositions comprising a metabolite described herein or bacterial species described herein
- Non-limiting examples of an excipient include a buffering agent, a diluent, a preservative, a stabilizer, a binding agent, a filler, a lubricant, a dispersion enhancer, a disintegrant, a lubricant, wetting agent, a glidant, a flavoring agent, a sweetener, and a coloring agent.
- tablets or capsules can be prepared by conventional means with excipients such as binding agents, fillers, lubricants, disintegrants, or wetting agents. Any of the compositions described herein can be administered to a subject to treat ASD as described herein.
- a composition as described herein can be formulated for oral delivery.
- the composition can be formulated as a tablet, a chewable tablet, a capsule, a stick pack, a powder, effervescent powder, or a liquid.
- the composition can be formulated as a tablet.
- the tablet is coated, for example, the tablet is coated with an enteric coating.
- the tablet is coated with a coating for timed release.
- the table is coated with a coating for immediate release. In some embodiments, the tablet is not coated.
- a composition can include coated beads that contain a metabolite described herein or a bacterial species described herein.
- a powder comprising the metabolite or bacterial species can be suspended or dissolved in a drinkable liquid such as water for administration.
- the composition is a solid composition.
- a composition described herein e.g., compositions comprising a metabolite described herein or bacterial species described herein
- a controlled release formulation can include a controlled release coating disposed over the metabolite or bacterial species.
- the controlled release coating is an enteric coating, a semi-enteric coating, a delayed release coating, or a pulsed release coating.
- a coating can be suitable if it provides an appropriate lag in active release (i.e., release of the metabolite or bacterial species).
- the composition can be formulated as a tablet that includes a coating (e.g., an enteric coating).
- the M3 consortium (Metabolite, Microbiome and the Mind) recruited a large cohort of 111 families with one ASD child and one neurotypical (NT) sibling in the same age range to minimize the impact of genetics, diet and environment. Severity of autism in ASD subjects was captured using the Mobile Autism Risk Assessment (MARA). In addition, 365 metadata features assessing inter- and intra- family variabilities were collected to permit further investigation of environmental factors’ influences on the ASD microbiome.
- Gut microbiome from stool samples was characterized at the DNA, RNA and metabolite levels using multi-omics technologies, including, 16S V4 rRNA region next generation sequencing (16S NGS), 16S V1-V9 rRNA PhyloChip® DNA micro-array (16S PC), whole-metagenome shotgun sequencing (MTG), metatranscriptomics (MTT) and metabolomics (MTB). See FIG.1.
- 16S V4 rRNA region next generation sequencing (16S NGS
- 16S V1-V9 rRNA PhyloChip® DNA micro-array (16S PC)
- MMG whole-metagenome shotgun sequencing
- MTT metatranscriptomics
- MTB metabolomics
- FIG. 6 shows the relative abundance of significantly different taxa between ASD and NT groups across the 3 time-points with FIG.6A at the genus level and FIG.6B at the species level (Kruskall Wallis test paired by family ID with padj ⁇ 0.05 in the 16S V4 data set).
- Anaerotignum genus consistently showed higher abundance in ASD across three timepoints and Blautia genus showed an opposite trend across the 3 time points.
- Blautia has been reported in several ASD studies as depleted in ASD subjects compared to NT. The decrease in Blautia genus detected in ASD children may be associated with constipation, which seems to provide evidence of the presence of gut dysbiosis (Inoue et al., 2019). Blautia wexlerea species was observed to be consistently lower abundance in ASD across three time points. This species shows anti-inflammatory properties (Ben ⁇ tez- Páez et al., 2020. mSystems.5:2, e00857-19). [00120] FIG.
- Metabolite A (5-dodecenoate) (FIG.7A) and Metabolite B (CEGABA) (FIG.7B).
- Metabolite A is a mono-unsaturated fatty acid (MUFA).
- MUFA mono-unsaturated fatty acid
- Other studies indicate a link between autism and MUFA, Bell et al. found that total MUFA were significantly reduced in regressive autism patients compared with controls (Bell et al.2010).
- Metabolite B is the intermediate of an alternative metabolic pathway in the biosynthesis of a neuromodulator.
- FIG. 8 shows the results of linking variation in metabolomic data with community composition by utilizing taxonomic, genomic, and metabolic information (Noecker et al. 2016. mSystems. 1:1, e00013-15).
- FIG. 8A are the putative bacterial contributors to variation in amino acids and other metabolites
- FIG.8B is a summary of bacterial contribution type of the putative bacterial contributors.
- the gene abundance from the microbial composition (16S V4) was predicted utilizing the software Piphillin (Iwai et al.2016.
- FIG. 9 shows pairwise correlation using Spearman test (Padj ⁇ 0.05 and
- Metabolite A significantly correlated with Blautia wexlerea, which is significantly depleted in the ASD group.
- Metabolite B significantly correlated with ASV 1597, which further associated with microbial genes involved in neuromodulator pathway.
- the following metabolites were identified: 1.
- Malate identified from sg_project_id UNFII_FLembo_BIRD18_0289 16S sequencing data based on the MelonnPan pipeline when using BioCyc and KEGG as the reference database.
- CEGABA Carboxyethyl aminobutyric acid (CEGABA) has been found depleted in the most severe cases of Autism Spectrum Disorder (51 subjects with a Mobile Autism Risk Assessment score ⁇ 8) compared to their neurotypical siblings in the M3 study. A Welch test (paired by family ID) was performed on log2 transformed data with zero imputed as the minimum value per metabolite to access differentially abundant metabolites between the groups.
- FIG.10 shows a volcano plot of the results of the Welch test (paired by family ID) comparing the metabolites abundance in the most severe cases of ASD and their neurotypical siblings. CEGABA was the most significantly different metabolite. See FIG. 7B. [00128] Comparing differences in ASD and NT, significant differences were found in compositions of 16S NGS at strain levels (Wald test) as well as higher taxonomical levels (Wilcoxon rank sum test) but not by 16S PC or MTG.
- Example 2 Effects of metabolites associated with autism spectrum disorder on gene transcription in brain tissue in mice.
- Metabolites identified in Example 1 were use in experiments to determine if the metabolites affected gene transcription patterns in the mouse brain or mouse behavior.
- mice were fed food mixed with 5-dodecanoate (5D), glycodeoxycholate (GDC), ursodeoxycholate (UDC), or control food (CTL) that did not have a supplemented metabolite.
- RNA sequencing Transcriptomics data was collected from the prefrontal cortex of 12-week old mice after consuming a low, medium, or high dosage of supplemented metabolites for two weeks. RNA sequencing used brain tissue to evaluate possible correlation between changes in relative changes in gene transcription with changes in behavior. The number of differentially expressed gene pathways at significance level of 0.05, 0.1, and 0.15 was determined (Table 1). The expression of many genes changed in mouse brain tissue due to supplementation with various metabolites or compounds. No changes in expression were observed in brain tissue from mice fed control food lacking a supplement. [00133] Table 1. Differentially Expressed Gene Pathways in Mouse Brain After Consuming Food Supplemented with Various Metabolites. [00134] Example 3.
- mice were fed 80% of their total food as non-supplemented food (chow) for 4 days. For the next two weeks, mice were fed 80% of their total food as non-supplemented food and the remaining 20% was supplemented with selected metabolites(s). Mice were fed on food supplemented with various metabolites including 5-dodecacenoate (5D), glycodeoxycholate (GDC), ursodeoxycholate (UDC), or a control food lacking a supplement (CTL). Mouse behavior was tested using an elevated plus maze (FIG. 13), a three-chamber sociability test, and tracking wheel usage.
- 5D 5-dodecacenoate
- GDC glycodeoxycholate
- UDC ursodeoxycholate
- CTL control food lacking a supplement
- mice were fed 80% of their total food as non-supplemented food and the remaining 20% was supplemented with the selected metabolites(s).
- Anxiogenic behavior was tested by tracking time spent in closed arms of an elevated plus maze. Control mice were fed food lacking a supplement. Mice fed food supplemented with 5D and UDC spent less time in the closed arms of the maze (FIG.14) and had lower active time in the closed arms of the maze than control mice (FIG.15). Mice fed food supplemented with GDC did not spend significantly more time in closed arms than control mice.
- Habituation over was tested with the elevated plus maze (FIG.16). Mice fed food supplemented with 5D or GDC showed habituation over three days.
- mice fed food supplemented with 5D or GDC showed lower total distance traveled and exploratory activity over three days (FIG.17).
- Mice fed food supplemented with a control metabolite did not habituate between days two and three.
- UDC did not decrease the total distance traveled on day three compared to day two, showing a lack of habituation. Significance was tested with an ANOVA test.
- Habituation was measured by tracking the amount of time spent in the center of the chamber (FIG.18). Mice fed food supplemented with 5D is significantly different from all other treatment groups, showing a trend for habituating to the center with an increase in time spent in the center of the chamber over time.
- mice did not habituate as they spent less time in the center of the chamber as time progressed.
- Active time was also measured as total ambulatory time and center ambulatory time. All mice showed less total ambulatory time over time (FIG.19), but mice fed food supplemented with 5D showed exploratory behavior with an increase in center ambulatory time over time (FIG.20).
- the effect of supplementation with the metabolites on sociability was measured with a three-chamber sociability test (FIG. 21). This chamber tested for responses to social novelty.
- mice fed food supplemented with 5D spent more time with a novel mouse (‘new’) than a mouse it had seen before (‘old’) (FIG.22), and of the different treatments, spent the most time with a new mouse (FIG.23).
- Table 2. Behavioral assay summary.
- mice fed with food supplemented with various metabolites were given a mouse wheel and distance traveled was tracked. All groups traveled significantly farther on average than the control group, although initial pace was the same (FIG.24; Table 3). Also, night-time activity increased after administering metabolites for GDC, UDC and 5D.
- FIG.25 shows an overall study design. Each sibling pair consisted of one ASD child and their respective TD sibling. Dietary, lifestyle, and other host variables were collected. The DADA2 pipeline was used to process the 16S V4 amplicon sequences. Samples from sibling pairs with ASD phenotypes unverified by parent reports or home videos were removed, leaving 432 samples.
- ASVs that significantly varied between timepoints in a Friedman test or were not present in 3% or more of the samples were removed.
- 117 ASVs were found to be significantly enriched in either the TD or ASD cohort.11 of those ASVs were identified by more than one of the contrast methods shown above. Abundance counts of these 11 significant taxa are used as predictors in Random Forest Models.
- METHODS [00148] Recruitment and Data Collection [00149] Families with two siblings, one previously diagnosed with ASD by a health care provider and one typically developing were recruited. Children between 23 months to 8 years old, and siblings had to be within 2 years of each other were recruited.
- ASD Autism Spectrum Disorder Diagnosis Verification
- MAA Mobile Autism Risk Assessment
- parents submitted a short video of their child with and child without ASD via encrypted file share to be rated for ASD symptoms on a set of 30 behavioral features. Scores across multiple raters were fed to previously published Machine Learning classifiers to predict ASD risk scores. By combining these risk scores with the parent-report screening tool (MARA), as well as parent-reported physician diagnosis, diagnosis was confirmed using majority rules consensus. Three children and their TD siblings were excluded for whom the consensus did not agree with original parent diagnosis.
- DNA was extracted from the pelleted stool samples using the MagAttract PowerMicrobiome DNA/RNA Kit (Qiagen) on the KingFisher Flex 96 (ThermoFisher), following manufacturer’s instructions. If DNA did not meet quality standards, an additional DNA clean-up procedure was performed with the Zymo ZR-96 DNA Clean-up kit. All samples were quantified via the Quant-iT PicoGreen dsDNA Assay Kit.
- the 16S rRNA V4 region was amplified with degenerate primers designed against conserved regions of the 16S rRNA V4 gene region, fused with Illumina adapters and indexing barcodes.
- strain level ASV assignment ASVs were mapped to a strain database (StrainSelect, secondgenome.com/platform/data-analysis-tools/strainselect on the World Wide Web, version 2019 (SS19)) using USEARCH (usearch_global).
- strainSelect secondgenome.com/platform/data-analysis-tools/strainselect on the World Wide Web, version 2019 (SS19)
- USEARCH usearch_global
- a Friedman test was used to model ASV abundance as dependent on timepoint for each individual, and ASVs that were significantly related to timepoint (p ⁇ 0.1) were removed.64 ASVs were removed from DESeq normalized data, 78 ASVs were removed from CSS normalized data, and 72 ASVs were removed from unnormalized data.
- ASVs are significantly associated with the ASD Phenotype, as determined by the union of at least two differential analysis methods [00170] Out of 834 total ASVs (Amplicon Sequence Variants, assigned using DADA2), 117 were identified to be significantly different between the ASD and TD cohorts by at least one of the contrast analysis methods used after normalization and filtration (DESeq2, MetagenomeSeq, and ANCOM, see methods). Out of the 117 ASVs found to be significant across time points, 37 belonged to the Lachnospiraceae family.
- Oscillospiraceae and Bacteroidaceae were the second most represented families with 10 ASVs belonging to each of these families.93 of the 117 ASVs were detected as significant by DESEQ2, 28 by MetagenomeSeq, and 4 by ANCOM. 45 ASVs were not associated with any lifestyle or dietary variables extracted from the questionnaires. Most notably, 11 ASVs were identified by at least 2 differential analysis methods. [00171] Table 4 summarizes the 11 ASVs with overlapping detection between two contrast methods independently, and their lifestyle/dietary associations if applicable. Two of these were solely associated with the ASD cohort, and no other dietary or metadata co- variate: one from the genus Holdemania and one from the family Lachnospiraceae.
- FIG. 26 shows total sum scaled abundance bar plots for the ASVs identified as significant by two methods. The ASV with the highest abundance among the 11 belonged to Blautia wexlerae with a relative abundance of almost 4% within the NT and around 2.5%-3% within the ASD cohort as shown in FIG. 26. ASVs from Bacteroides thetaiotaomicron and a different Blautia ASV were among the next highest abundances with values around 0.005%-0.01%.
- This metric was used to measure changes in anxiety within the same individual across time, allowing full leverage the longitudinal nature of the data to identify specific ASVs associated with reported anxiety.10 ASVs significantly negatively correlated and 1 ASV positively correlated with increasing anxiety (FIGs.28A-28B, Table 6). Two ASVs from the species A. butyriciproducens, a butyrate producing bacteria, were both negatively correlated with anxiety. Six of the 10 ASVs negatively correlated with anxiety were members of the Lachnospiraceae family.
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